CN111378007B - Method for preparing palippivir by using second-generation Hoveyda-Grubbs catalyst - Google Patents
Method for preparing palippivir by using second-generation Hoveyda-Grubbs catalyst Download PDFInfo
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- ZRPFJAPZDXQHSM-UHFFFAOYSA-L 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazole;dichloro-[(2-propan-2-yloxyphenyl)methylidene]ruthenium Chemical compound CC(C)OC1=CC=CC=C1C=[Ru](Cl)(Cl)=C1N(C=2C(=CC(C)=CC=2C)C)CCN1C1=C(C)C=C(C)C=C1C ZRPFJAPZDXQHSM-UHFFFAOYSA-L 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 57
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 14
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 238000010511 deprotection reaction Methods 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- 238000007112 amidation reaction Methods 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 238000007363 ring formation reaction Methods 0.000 claims description 6
- 230000009435 amidation Effects 0.000 claims description 5
- 239000011261 inert gas Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- BENKAPCDIOILGV-RQJHMYQMSA-N (2s,4r)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(O)=O BENKAPCDIOILGV-RQJHMYQMSA-N 0.000 claims description 3
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical group Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims 1
- 239000012629 purifying agent Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000003960 organic solvent Substances 0.000 abstract description 2
- 230000003213 activating effect Effects 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 21
- 239000000543 intermediate Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 241000711549 Hepacivirus C Species 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- 101710144111 Non-structural protein 3 Proteins 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000005265 energy consumption Methods 0.000 description 3
- -1 hexafluorophosphate Chemical compound 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 102100038132 Endogenous retrovirus group K member 6 Pro protein Human genes 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000012964 benzotriazole Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RBYJWCRKFLGNDB-UHFFFAOYSA-N 5-methylpyrazine-2-carboxylic acid Chemical compound CC1=CN=C(C(O)=O)C=N1 RBYJWCRKFLGNDB-UHFFFAOYSA-N 0.000 description 1
- 101710167800 Capsid assembly scaffolding protein Proteins 0.000 description 1
- 101710132601 Capsid protein Proteins 0.000 description 1
- 101710118188 DNA-binding protein HU-alpha Proteins 0.000 description 1
- 101710091045 Envelope protein Proteins 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 101710144128 Non-structural protein 2 Proteins 0.000 description 1
- 101800001020 Non-structural protein 4A Proteins 0.000 description 1
- 101800001019 Non-structural protein 4B Proteins 0.000 description 1
- 101800001014 Non-structural protein 5A Proteins 0.000 description 1
- 101710199667 Nuclear export protein Proteins 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 108010076039 Polyproteins Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 101710188315 Protein X Proteins 0.000 description 1
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000011985 first-generation catalyst Substances 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 239000011987 hoveyda–grubbs catalyst Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000029302 virus maturation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for preparing paliprovir by using a second-generation Hoveyda-Grubbs catalyst. And (2) activating and rearranging the C-C of the ring-opening intermediate I by using a second-generation Hoveyda-Grubbs catalyst to form a ring-closing intermediate II, wherein the dosage of the second-generation Hoveyda-Grubbs catalyst is 0.5-1mol% of that of the ring-opening intermediate I in the reaction process, the solvent is ethyl acetate, the reaction temperature is kept at 70-75 ℃, the dosage of the catalyst is less, the process conditions are mild and energy-saving, and the organic solvent is safe and environment-friendly. The preparation method is economic, environment-friendly and low in cost, and is beneficial to industrial production.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, and particularly relates to a method for preparing paliprovir by using a second-generation Hoveyda-Grubbs catalyst.
Background
Hepatitis C Virus (HCV) is a single-stranded RNA virus whose core proteins include envelope proteins E1 and E2, membrane-bound protein p7 and nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B, of which protease NS3/4A plays an important role in the process of virus maturation and has been confirmed to be one of the effective targets for the discovery of hepatitis c drugs.
Palipoprevir, a direct-acting drug for combination therapy against HCV, is an HCV NS3/4A protease inhibitor that inhibits depolymerization of the polyprotein required for viral replication. The palipoprevir is one of main components in the ABT triple anti-hepatitis C drug, has the CAS number of 1216941-48-8, and has the following structure:
in the existing preparation method of the paliprovir, a first-generation Hoveyda-Grubbs catalyst is mostly adopted, and in the process of synthesizing a closed-loop intermediate II by using a ring-opening intermediate I, the catalyst consumption is up to 5 mol%, and the price is high, so that the production cost is high; in addition, highly toxic dichloroethane is used as a solvent in the catalysis process, which is not favorable for safety and environmental protection; meanwhile, the catalytic reaction has extremely high requirement on temperature, and the high temperature of 100 ℃ needs to be kept for a long time, so that the energy consumption is huge. Therefore, in order to solve the problems of high use cost of the catalyst, environmental pollution of the catalytic process and high energy consumption in the catalytic process in the prior art, a new catalytic process is urgently needed to be found, and the technical barrier of preparing the palicepvir is overcome.
Disclosure of Invention
The invention aims to provide a method for preparing palippivir by using a second-generation Hoveyda-Grubbs catalyst, so as to solve the defects of the prior art.
The invention adopts the following technical scheme:
a method for preparing paliprovir by using a second-generation Hoveyda-Grubbs catalyst comprises the steps of enabling a ring-opening intermediate I to be activated and rearranged by the second-generation Hoveyda-Grubbs catalyst to form a ring-closing intermediate II, and then carrying out amino deprotection and amidation treatment to obtain the paliprovir;
the reaction route is as follows:
further, under the protection of inert gas, the ring-opened intermediate I is activated and rearranged by a second generation Hoveyda-Grubbs catalyst in a solvent to form a closed ring, and then the closed ring intermediate II is obtained through post-treatment.
Further, the second generation Hoveyda-Grubbs catalyst is used in the ring-opening reaction system in an amount of 0.5 to 1mol% based on the ring-opening intermediate I.
Further, the solvent in the ring-closure reaction system is ethyl acetate.
Further, the reaction temperature in the ring-closing reaction system is 70-75 ℃, the reaction time is 20-30 hours, and the reaction time comprises the adding time of the second generation Hoveyda-Grubbs catalyst.
Further, the inert gas in the ring-closing reaction system is nitrogen.
Further, the post-treatment after the ring-closure reaction includes removal of the solvent, precipitation of a solid, filtration, and drying.
Further, the Boc-L-hydroxyproline is used as a raw material to obtain a ring-opening intermediate I, and the reaction route is as follows:
further, in the amino deprotection reaction system, the organic reagent is dichloromethane, the amino deprotection reagent is a hydrogen chloride ethanol solution, and the post-treatment solid precipitation reagent is methyl tert-butyl ether.
Further, in the amidation reaction system, the organic purifying reagents are acetonitrile and ethyl acetate.
The invention has the beneficial effects that:
the invention adopts a second-generation Hoveyda-Grubbs catalyst to activate and rearrange C ═ C of the ring-opening intermediate I to form a ring-closing intermediate II, and then the plepivvir is prepared by amino deprotection and amidation treatment. The second-generation Hoveyda-Grubbs catalyst is adopted to activate and rearrange C ═ C of the ring-opening intermediate I to form a ring-closing intermediate II, the dosage of the second-generation Hoveyda-Grubbs catalyst in the reaction process is 0.5-1mol% of that of the ring-opening intermediate I, the solvent is ethyl acetate, the reaction temperature is kept at 70-75 ℃, the dosage of the catalyst is small, the process conditions are mild and energy-saving, the organic solvent is safe and environment-friendly, and the problems of large dosage of the catalyst, large toxicity of the solvent and high reaction energy consumption in the existing preparation of the palipopvirs are solved. The preparation method is economic, environment-friendly and low in cost, and is beneficial to industrial production.
The purity and yield of the ring-closed intermediate II and the final product of the pleipvir obtained by the method are slightly improved compared with those of a first-generation catalyst, and the method is favorable for purifying the product in the post-treatment process.
Detailed Description
The present invention will be further explained with reference to examples. The following examples are provided only for illustrating the present invention and are not intended to limit the scope of the present invention.
The chemicals used in the following examples are conventional commercial reagents and the stirring involved can be 150 rpm.
Example 1: synthesis of Ring-opened intermediate I
Adding 1.0kg Boc-L-hydroxyproline into 30L dimethyl sulfoxide, stirring at room temperature (25-30 deg.C) for 10 min, cooling to 8-10 deg.C, and gradually adding 1.2kg t-butyl during 30 minStirring potassium alcoholate at 30 ℃ for 2 hours, cooling to 8-10 ℃, then gradually adding 6-chlorophenamidine in an amount of 1.1kg within 30 minutes, stirring overnight at 30 ℃, monitoring by TLC until the reaction is complete, adding 30L deionized water at 25 ℃, stirring for 15 minutes, washing with ethyl acetate for 4 times, adjusting the pH value of a water layer to 1 by 1N HCL after the temperature of the water layer is cooled to 10 ℃, adding ethyl acetate for extraction, separating an ethyl acetate layer, concentrating to obtain an initial product, adding petroleum ether, stirring for 12 hours, and filtering to obtain a solid. Adding 17L of dichloromethane into the solid at room temperature (25-30 ℃), cooling to 10 ℃, adding 1.32kg of N, N-diisopropylethylamine, stirring for 10 minutes, adding 1.43kg of 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate and 915g of intermediate a, stirring at 27 ℃ for reaction for 12 hours, adding 7L of water after the reaction is completed, adding 500g of anhydrous Na2SO4Drying and separating an organic phase, evaporating a solvent at 35 ℃ to obtain a thick brown liquid, adding 10L of isopropanol to dilute and disperse the thick brown liquid, stirring for 16 hours at 27 ℃, separating out a solid, filtering, cleaning the solid with 500ml of isopropanol, drying for 2 hours in vacuum, baking for 3 hours at 60 ℃, adding 16L of dichloromethane, observing the color to become brown, cooling to 10 ℃, adding 7.8L of 5mol/L hydrogen chloride ethanol solution, stirring for 3 hours at room temperature (25-30 ℃), monitoring the reaction by TLC, concentrating to obtain 1.6Kg of solid at 50 ℃, adding 15L of dichloromethane at 30 ℃, cooling to 0-5 ℃, adding 1.7Kg of N-methylmorpholine, adding 79g of 1-hydroxybenzotriazole and 1.21Kg of 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate at 3 ℃, stirring for 10 min, adding 791g of intermediate b within 5 min, stirring at 0 ℃ for 3 h, monitoring the reaction completion by TCL, adding 5.3L of water, stirring for 10 min, removing the aqueous layer, adding 12L of 5 wt% citric acid solution to wash the organic phase, and adding 5.3L of water to wash the organic phase. With anhydrous Na2SO4Drying, concentrating at 40 deg.C to obtain concentrate, adding 15L 5 v/v% isopropanol/petroleum ether solution, stirring at 25 deg.C for 16 hr to precipitate solid, filtering to obtain 1.8kg solid product, and purifying with 25 v/v% ethyl acetate/petroleum ether column to obtain 1.5kg purified product with purity of 97.50% by HPLC.
The intermediates a and b can be purchased directly on the market, and the structural formula is as follows:
structure of intermediate a:
the structural formula of the intermediate b is as follows:
example 2: preparation of ring-closed intermediate II by second-generation Hoveyda-Grubbs catalytic ring-closing reaction
In a 500L reactor 320L of ethyl acetate were placed and purged with nitrogen for 20 hours to drive off the air remaining in the solvent, and under a nitrogen blanket, 800g of the solid product of example 1 above was added, the solution was heated with stirring at 75 ℃ and refluxed, 3.09g of the second generation Hoveyda-Grubbs catalyst was gradually added over 5 hours, the reflux was continued with stirring for 20 hours, and the reaction was monitored by TLC until completion. Concentrating at 55 deg.C to remove solvent to obtain 2kg crude product, adding 6L ethyl acetate at 26 deg.C, stirring to dissolve the mixture, filtering the mixture through a silica gel bed, washing the silica gel bed with ethyl acetate, concentrating at 50 deg.C to remove solvent to obtain 1.5kg concentrated brown liquid, adding 2L 10 v/v% ethyl acetate/petroleum ether, stirring and dispersing, stirring at 26 deg.C for 16 hr to precipitate solid, filtering, adding 500ml10v v/v% ethyl acetate/petroleum ether to wash the solid, vacuum drying at 40 deg.C for 1 hr, drying in air at 25 deg.C for 12 hr until ethyl acetate is completely removed to obtain 728g product with purity of 83.30 by HPLC.
Example 3: the ring-closed intermediate II is subjected to amino deprotection to synthesize an intermediate III
50g of the product from example 2 above are added to 500ml of dichloromethane and stirred until a brown clear solution is obtained, 100ml of a 5mol/L ethanolic hydrogen chloride solution are added at 10-15 ℃ over 15 minutes, the mixture is stirred at 25 ℃ for 2 hours, the reaction is monitored by TLC for completion, dichloromethane is distilled off at 40 ℃, 250ml of methyl tert-butyl ether is added at 25 ℃, the mixture is filtered after stirring for 30 minutes, the solid is washed with 50ml of methyl tert-butyl ether, dried under vacuum at 40 ℃ for 1 hour and dried in air at 25 ℃ for 12 hours, 65g of the product are obtained, the purity is 82.00% by HPLC.
EXAMPLE 4 preparation of Periplavir from intermediate III by amidation
At 30 ℃, 732ml of acetonitrile is added with 18.5g of 5-methylpyrazine-2-carboxylic acid, cooled to 0 ℃ to 5 ℃, added with 86.5g of N, N-diisopropylethylamine and stirred for 5 minutes, added with 1.8g of 1-hydroxybenzotriazole and stirred for 5 minutes, then added with 50.7g of 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate and stirred for 5 minutes. 91.5g of the product from example 3 above were added over 15 minutes and the reaction was monitored by TLC at 0-5 ℃. After completion of the reaction, 500ml of ethyl acetate and 500ml of deionized water were added, the black organic phase was separated, the aqueous layer was extracted with 500ml of ethyl acetate, the organic layers were combined and washed with anhydrous Na2SO4Drying, concentrating at 40 deg.C to obtain 160g crude product, purifying with ethyl acetate/petroleum ether column at volume ratio of 1:1 to obtain 100g crude product, adding 300ml acetonitrile at 27 deg.C, stirring for dispersing, stirring for 12 hr to separate out solid, filtering, washing with 50ml acetonitrile, vacuum drying at 40 deg.C for 10 min, oven drying at 70 deg.C for 3 hr to obtain 60g solid product with purity of 99.13% by HPLC.
Claims (5)
1. A method for preparing paliprovir by using a second-generation Hoveyda-Grubbs catalyst is characterized in that a ring-opening intermediate I is activated and rearranged by the second-generation Hoveyda-Grubbs catalyst by C = C to form a ring-closing intermediate II, and then amino deprotection and amidation treatment are carried out to obtain the paliprovir; under the protection of inert gas, the ring-opening intermediate I is activated and rearranged by a second generation Hoveyda-Grubbs catalyst in a solvent to form a closed ring after C = C, and then a closed-ring intermediate II is obtained through post-treatment; the dosage of the second generation Hoveyda-Grubbs catalyst in the closed-loop reaction system is 0.5-1mol% of that of the ring-opening intermediate I, the solvent in the closed-loop reaction system adopts ethyl acetate, the reaction temperature in the closed-loop reaction system is 70-75 ℃, the reaction time is 20-30 hours, the reaction time comprises the adding time of the second generation Hoveyda-Grubbs catalyst, and the post-treatment after the closed-loop reaction comprises the steps of removing the solvent, precipitating solids, filtering and drying;
the reaction route is as follows:
2. the process of claim 1, wherein the inert gas in the ring-closing reaction system is nitrogen.
3. The method for preparing palippivir by using the second generation Hoveyda-Grubbs catalyst as claimed in claim 1, wherein the ring-opened intermediate I is obtained by using Boc-L-hydroxyproline as a raw material, and the reaction route is as follows:
4. the method for preparing palippivir by using the second generation Hoveyda-Grubbs catalyst as claimed in claim 1, wherein in the amino deprotection reaction system, the organic reagent is dichloromethane, the amino deprotection reagent is hydrogen chloride ethanol solution, and the post-treatment solid precipitation reagent is methyl tert-butyl ether.
5. The method according to claim 1, wherein the organic purifying agent in the amidation treatment reaction system is acetonitrile or ethyl acetate.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008132962A1 (en) * | 2007-04-20 | 2008-11-06 | Niigata University | Olefin matathesis catalyst and process for producing olefin reaction product through metathesis reaction with the same |
| WO2017064680A1 (en) * | 2015-10-16 | 2017-04-20 | Lupin Limited | An improved process for the preparation of simeprevir sodium and intermediate thereof |
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| PL379879A1 (en) * | 2006-06-07 | 2007-12-10 | Umicore Ag & Co.Kg. | Ruthenium and osmium complex, the manner of their production and their application as (pre)catalytic agent of metathesis reaction |
| UY32099A (en) * | 2008-09-11 | 2010-04-30 | Enanta Pharm Inc | HEPATITIS C SERINA PROTEASAS MACROCYCLIC INHIBITORS |
| CN107383021A (en) * | 2017-08-01 | 2017-11-24 | 安徽拜善晟制药有限公司 | A kind of bulk drug Pa Lipuwei preparation method |
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| WO2008132962A1 (en) * | 2007-04-20 | 2008-11-06 | Niigata University | Olefin matathesis catalyst and process for producing olefin reaction product through metathesis reaction with the same |
| WO2017064680A1 (en) * | 2015-10-16 | 2017-04-20 | Lupin Limited | An improved process for the preparation of simeprevir sodium and intermediate thereof |
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